A Tailored Approach to Prostate Cancer Therapy Based upon PTEN Status
Final rept. 15 Apr 2011-14 Oct 2012
JEFFERSON MEDICAL COLL PHILADELPHIA PA
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The purpose of this study was to investigate the hypothesis that PTEN null prostate cancer cells and tumors will exhibit increased radiosensitivity to inhibition of the DNA repair enzyme, PARP, compared to wild-type PTEN-expressing cells and tumors, resulting in increased efficacy of radiotherapy and chemotherapy. The specific objectives of this study were to 1 determine the effect of PARP inhibition on the cellular response to ionizing radiation or docetaxel in DU145 PTEN wild-type vs. PC-3 PTEN-null cells. and 2 determine the efficacy of PARP inhibition in combination with radiotherapy or docetaxel in DU145 and PC-3 prostate cancer xenograft models. Radiosensitization was measured in DU145 cells and PC-3 cells by H2AX foci formation and disappearance, quantitation of olive tail moment in comet assay, clonogenic cell survival and apoptosis assay. Additionally, qPCR was performed to assess changes in DNA repair gene expression following radiation andor drug treatments. H2AX foci assays revealed that ABT888 in combination with radiation therapy RT increased the level of DNA damage compared to drug alone and RTX alone in both cell lines, and that the combination inhibited DNA repair in PC-3 cells but not in DU145 cells. Apoptosis assays indicated that DU145 cells were more susceptible than PC-3 cells to apoptosis induction by monotherapy with ABT888, docetaxel or RT. However, triple modality treatment with ABT888, docetaxel and RT increased apoptosis similarly in both cell lines. Clonogeic assays revealed that although DU145 was more radioresistant than PC-3 cells, ABT888 similarly radiosensitized both cell lines. qPCR revealed prolonged upregulation of the RAD family members in PC-3 cells. In vivo studies of tumor growth confirmed that the PC-3 xenografts, lacking PTEN, were more sensitive to RT than the DU145 xenografts.
- Medicine and Medical Research